The Global Urate Genetics Consortium has validated 28 SNP associations in serum urate. Some of these loci harbor urate transporter genes, whereas for most other loci the causal genes remain unresolved. GWASdiscovers associated SNPs in statistical linkage disequilibrium with causal variants, not the causal variants themselves. Knowledge of the causal variants, their mechanisms of action, and interactions with other loci are needed to pinpoint the causal genes. This will lead to understanding of the precise biology of dysfunction leading to hyperuricemia and gout, and will identify new therapeutic targets. We propose to conduct fine-mapping and causal variant analyses in the serum urate loci, and to conduct focused functional assays of strong candidate functional variants. Advances in sample acquisition,data generation and statistical analysis create the opportunity to fine-map urate loci in multiple ethnicities, an to characterize the allelic spectrum of functional, putatively causal variation. We will utilize tree serum urate/gout cohorts of European, African American, Hispanic/Latino and Polynesian ancestries, whose differing patterns of linkage disequilibrium will facilitate the localization of genetic signal (total N >5,000). The genetic data include targeted next- generation sequence of genes across the serum urate loci, and GWAS and Exome-chip genotypes with 1000 Genomes imputation, representing sequence-level data for common variants and for low- frequency variation for coding regions of candidate genes.Low-frequency variants are of particular interest for functional follow up, since they are expected to have larger effect sizes.Here, in Aim 1, we propose to conduct meta-analysis across cohorts, and joint cross-ethnic Bayesian inference of the 'credible set'of causal variants. Annotation, bioinformatic and functional genomic data will be incorporated into variants'prior probabilities in the Bayesian framework.A prioritized 'credible set'of causal variants will be the prima facie deliverable of this project. In serum uate and hyperuricemia, robust and inexpensive functional models can be used to assay the functional consequences of candidate causal variants in urate transport, and therefore to validate and characterize the mechanism of action (e.g. increased vs decreased urate transport).
In Aim 2, we propose to useurate transport in Xenopus oocytes to characterize the functional impacts of the highest-priority putative causal variants for specific urate transporter. These experiments will validate and synergize with the genetic analyses described above. In addition to urate transporter coding variants, we can assay directly interacting proteins by co-expressing them in oocytes and measuring effects on urate transport. This project will deliver ex vivo functional consequences of a set of serum urate causal variants.
Gout disease affects over 8 million people in the US and across the world, and many chromosomal locations that affect uric acid levels and gout have been discovered~ however, the functional genes and mutations remain to be characterized.This project will identify putative/candidate functional genes and mutations in these loci, in part through genetic analyses of individuals from under-represented ethnicities, and willexperimentally verify their functional effects. The results will facilitate the design of new therapies for hyperuricemia and gout, and will help to address disparities in health and biomedical research.
|Tanner, Callum; Boocock, James; Stahl, Eli A et al. (2017) Population-Specific Resequencing Associates the ATP-Binding Cassette Subfamily C Member 4 Gene With Gout in New Zealand M?ori and Pacific Men. Arthritis Rheumatol 69:1461-1469|
|Mandal, Asim K; Mercado, Adriana; Foster, Andria et al. (2017) Uricosuric targets of tranilast. Pharmacol Res Perspect 5:e00291|
|Rasheed, Humaira; McKinney, Cushla; Stamp, Lisa K et al. (2016) The Toll-Like Receptor 4 (TLR4) Variant rs2149356 and Risk of Gout in European and Polynesian Sample Sets. PLoS One 11:e0147939|